The goal of this study is to increase our understanding of the mechanisms by which bisposphonates can target osteoblasts to increase bone ingrowth into implant porosities and improve implant fixation. In this application, we will investigate the role of bisposphonates in regulating new bone in complementary in-vivo and in-vitro experimental models. Specific Aim 1 ill test the hypothesis that bisposphonates increase net bone growth into porous implants. We will investigate the effect of bisposphonates on the dynamics of bone formation and resorption using an in-vivo experimental model. A rabbit model employing intramedullary porous implants will be used to assess the effect of bisposphonates on the indices of bone remodeling. Specific Aim #2 will test the hypothesis that bisposphonates stimulate osteoblastic proliferation and maturation. Two in-vitro model systems using osteoblast-like cells at different stages of differentiation and maturation will be used to localize the effects of bisposphonates on the anabolic indices of osteoblast function. We will probe primary human trabecular bone cells as well as osteoblastic cell lines representing different stages of differentiation and maturation such as C3EH10T1/2, the murine pre-osteoblast clone MC3T3-E1, and the human osteosarcoma cell lines SAOS-2 and MG-63. Primary bone cell models will be used to identify the phenotypic stages at which bisposphonates affect osteoblast lineage cells. Together, these model systems will be used to investigate the effect of bisposphonates on the commitment of mesenchymally derived cells to the osteoblast lineage, mitogenic growth of osteoblast precursors, expression of the differentiated osteoblast phenotype, expression and synthesis of bone-related proteins (osteocalcin, bone sialoprotein) and mineralization of extracellular matrix. Knowledge gained from this study will advanced our understanding of the mechanisms by which bisphosphonate can increase bone formation and enhance orthopaedic implant fixation; and lead to the development of therapeutic interventions aimed at improving bone ingrowth, limit access for the wear debris to the bone-implant and simultaneously prevent osteolysis around joint replacements.